WO2017149858A1 - Agent antiviral et aliment antiviral - Google Patents

Agent antiviral et aliment antiviral Download PDF

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Publication number
WO2017149858A1
WO2017149858A1 PCT/JP2016/084571 JP2016084571W WO2017149858A1 WO 2017149858 A1 WO2017149858 A1 WO 2017149858A1 JP 2016084571 W JP2016084571 W JP 2016084571W WO 2017149858 A1 WO2017149858 A1 WO 2017149858A1
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WIPO (PCT)
Prior art keywords
euglena
virus
paramylon
antiviral
antiviral agent
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PCT/JP2016/084571
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English (en)
Japanese (ja)
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綾香 中島
鈴木　健吾
裕二 伊勢川
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株式会社ユーグレナ
学校法人武庫川学院
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Application filed by 株式会社ユーグレナ, 学校法人武庫川学院 filed Critical 株式会社ユーグレナ
Priority to JP2016569079A priority Critical patent/JP6114484B1/ja
Priority to CN201680082968.0A priority patent/CN108697741B/zh
Priority to SG11201807430WA priority patent/SG11201807430WA/en
Priority to US16/079,609 priority patent/US20190054127A1/en
Publication of WO2017149858A1 publication Critical patent/WO2017149858A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/68—Protozoa, e.g. flagella, amoebas, sporozoans, plasmodium or toxoplasma
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/127—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/12—Unicellular algae; Culture media therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/04—Polysaccharides, i.e. compounds containing more than five saccharide radicals attached to each other by glycosidic bonds

Definitions

  • the present invention relates to a novel antiviral agent and antiviral food, and more particularly to an antiviral agent and antiviral food that contain Euglena-derived substances as active ingredients and are used for the prevention or treatment of viral infections.
  • a viral infection is an infectious disease caused by a virus that is a pathogen that exists in the environment (air, water, soil, animals, etc.) entering the human body.
  • a virus is a small parasite generally having a size of about 0.02 to 0.3 ⁇ m, and is mainly composed of a protein shell (capsid) and a nucleic acid (RNA or DNA) inside the shell. Yes. Viruses are completely cell dependent for their replication and first adsorb to host cells and enter the cells. Then, DNA or RNA is released (unshelled) in the cell and replicated, and a specific enzyme is required in the process.
  • RNA viruses influenza viruses that cause respiratory diseases as typical viruses cause digestive diseases. Rotavirus and norovirus are known.
  • Rotavirus is a virus that causes infectious gastroenteritis, a digestive tract disease, and is generally known as a cause of infant diarrhea and vomiting diarrhea.
  • infant diarrhea seen in winter is a severe diarrheal disease that mainly causes fever, vomiting, diarrhea and dehydration in young children under 2 years old.
  • the annual number of patients with rotavirus gastroenteritis is about 800,000 and the number of hospitalizations is about 70 to 80,000, and several deaths are reported every year.
  • Rotavirus has a very strong infectivity, and even in advanced countries with a sanitary environment, it is considered that almost 100% of humans will be infected with rotavirus once by the age of five.
  • Non-Patent Document 1 In the United States, more than 500,000 people visit each year mainly for symptoms of diarrhea, especially children are prone to severe diarrhea, and about 10% of affected patients are said to be hospitalized. Although there seems to be regional differences, it is thought that about 700,000 people die every year worldwide (see Non-Patent Document 1). According to epidemiological surveys in developed countries, improvement in hygiene cannot reduce the prevalence of rotavirus. In addition, although vaccines against rotavirus have been developed, there are ineffective types and recombinants of vaccines, and countermeasures are required. Therefore, development of a rotavirus therapeutic agent with a novel mechanism is expected.
  • norovirus is a virus that causes infectious gastroenteritis, a gastrointestinal disease, which causes food poisoning due to eating oysters and other shellfish, as well as infected human feces and vomit, or dry them Oral infection through dust coming out of things.
  • Outbreaks of norovirus genus occur sporadically in schools, infant centers, and elderly facilities around the world, and there are cases where fatal death occurs due to dehydration.
  • Norovirus infections have been on the rise in recent years, and noroviruses are often mutated to mutate to infect humans from person to person, and are often endemic because they do not have antibodies against new types of noroviruses.
  • some of the vaccines against Norovirus have been found to be effective, but they are still under development, and development of Norovirus vaccines and development of Norovirus therapeutic agents with new mechanisms are expected.
  • Euglena (genus name: Euglena, Japanese name: Euglena) attracts attention as a biological resource that is expected to be used as food, feed, fuel, and the like.
  • Euglena has 59 kinds of nutrients that correspond to most of the nutrients necessary for humans to live, such as vitamins, minerals, amino acids, and unsaturated fatty acids, and as a supplement to take a variety of nutrients in a balanced manner.
  • the possibility of use as a food supply source in poverty areas where the necessary nutrients cannot be ingested has been proposed.
  • Euglena is located at the bottom of the food chain, and it is difficult to mass culture because it is preyed by predators and culture conditions such as light, temperature conditions, and stirring speed are difficult compared to other microorganisms.
  • a mass culture technique has been established, which has opened the way for the mass supply of Euglena and paramylon extracted from Euglena.
  • Euglena is a unique organism that possesses the animal nature of flagellar movement and at the same time has chloroplasts as a plant and performs photosynthesis, and Euglena itself and substances derived from Euglena are expected to have many functions. ing. Therefore, it is desired to elucidate the function of Euglena-derived substances such as Euglena and Paramylon that can be supplied in large quantities, and the mechanism of functional expression, and to develop a method for using these substances.
  • Patent Document 1 discloses a therapeutic agent for retrovirus infections containing sulfated paramylon obtained by sulfating euglena-derived paramylon as an active ingredient. Only a part of the antiviral activity of these Euglena-derived substances has been clarified, and it is desired to elucidate functions other than those described above and to develop methods for using these substances.
  • the present invention has been made in view of the above problems, and an object of the present invention is to provide a novel antiviral agent and antiviral food. Another object of the present invention is to provide an antiviral agent and an antiviral food which are novel uses of Euglena-derived substances.
  • Euglena-derived substances have an action of inhibiting the growth of RNA viruses having no envelope, particularly rotaviruses and noroviruses.
  • these viruses adsorb to host cells in the body and enter the cells, release RNA in the cells (unshelling) and replicate, and the replicated virus is released from the host cells and proliferates.
  • the present inventors have clarified that Euglena-derived substances inhibit the adsorption of viruses to host cells in the growth mechanism of these viruses, and inhibit the replication and release of the viruses in the host cells. It was clarified that the present invention was made.
  • the present inventors have clarified that Euglena-derived substances inhibit the activity of binding proteins and specific enzymes required during the adsorption and replication of these viruses in the growth mechanism of rotavirus and norovirus.
  • the present invention has been achieved.
  • the above-mentioned problem is solved by being used for the prevention or treatment of RNA virus infection that contains Euglena-derived substance as an active ingredient and does not have an envelope.
  • the RNA virus having no envelope may be a virus belonging to the family Reoviridae, and more preferably a rotavirus among the viruses belonging to the family Reoviridae.
  • the Euglena-derived substance is preferably a hot water extract of Euglena.
  • the Euglena-derived substance may be an alkali-treated product obtained by subjecting paramylon to an alkali treatment. As described above, by optimizing the extract of the Euglena-derived substance and the concentration of the extract, the effect of inhibiting RNA virus growth is further improved.
  • a virus generally adsorbs to a host cell in a living body and enters the cell, and RNA is released (unshelled) in the cell to be replicated, and the replicated virus is released from the host cell.
  • the extract of the present invention can exert antiviral activity at the time of adsorption to the host cell in order to inhibit virus growth. Therefore, for example, it is possible to know to what time the virus growth has progressed and to administer the antiviral agent at the optimal administration timing to a patient with viral infection.
  • an Euglena-derived substance as an active ingredient, and an antiviral agent used for the prevention or treatment of infectious gastroenteritis with a virus as a pathogen, or an antiviral agent used for the prevention or improvement of an RNA virus infection that does not have an envelope.
  • Viral foods can also be provided.
  • a novel antiviral agent and antiviral food can be provided. Moreover, the antiviral agent and antiviral food used as the novel utilization method of a Euglena origin substance can be provided.
  • the present embodiment is an invention of an antiviral agent characterized in that a Euglena-derived substance is used as an active ingredient and is used for the prevention or treatment of a viral infection by inhibiting the growth of a virus in the human body by administration to a human. It is about. More specifically, the present invention relates to an invention of an antiviral agent characterized by exhibiting antiviral activity at the time of virus adsorption to a host cell and the time of replication / release in order to inhibit virus growth.
  • Viruses are roughly classified into DNA viruses and RNA viruses depending on whether the genome is DNA or RNA.
  • DNA viruses can be mainly classified into two types depending on whether the DNA is single-stranded or double-stranded. Specifically, Parvoviridae and the like exist as single-stranded DNA viruses (those that do not have an envelope), and herpesviridae and poxviruses as double-stranded DNA viruses that have an envelope.
  • the family includes the family and the hepadnaviridae, and viruses such as the adenoviridae and the papillomaviridae exist without the envelope.
  • Examples of viral diseases caused by single-stranded DNA viruses include human parvo B19 (contagious erythema), and examples of viral diseases caused by double-stranded DNA viruses include herpes simplex (gingivitis). Labial herpes, genital herpes virus infection), chickenpox / zoster, pressure ulcer, hepatitis B, adeno (pharyngeal conjunctival fever, acute hemorrhagic conjunctivitis, epidemic keratoconjunctivitis), human papilloma and the like.
  • RNA virus is single-stranded or double-stranded, or in the case of a single-stranded RNA virus, whether the sense of the genome is positive (+) or negative (-) Can be classified mainly into three categories. Specifically, firstly, as single-stranded RNA viruses (with envelopes), viruses such as orthomyxoviridae, rhabdoviridae, paramyxoviridae, filoviridae, bunyaviridae and arenaviridae Exists.
  • the influenza virus belongs to the Orthomyxoviridae family.
  • Viral diseases caused by these single-stranded RNA viruses include influenza, avian influenza, rabies, measles, mumps (mumps), RS (respiratory infection), Ebola (hemorrhagic fever) , Marburg (haemorrhagic fever), Crimea-Congo haemorrhagic fever, SFTS, Lassa (haemorrhagic fever), Junin / Sabia / Ganarit / Machupo (haemorrhagic fever) and the like.
  • Flaviviridae As the single-stranded + strand RNA viruses, there are Flaviviridae, Coronaviridae, Togaviridae, Retroviridae, etc. having envelopes, and Caliciviridae and Picoviruses having no envelopes. There are viruses such as Lunaviridae. Norovirus belongs to the Caliciviridae family.
  • Viral diseases caused by these single-stranded + strand RNA viruses include dengue, West Nile, Japanese encephalitis, hepatitis C, yellow fever, SARS corona, MERS corona, rubella, human immunodeficiency (AIDS), human T Lymphophilic (adult T-cell leukemia), hepatitis E, noro (infectious gastroenteritis), polio (acute leukomyelitis), hepatitis A, coxsackie (hand-foot-and-mouth disease, herpangina), rhino (cold), etc. It is done.
  • AIDS human immunodeficiency
  • human T Lymphophilic adult T-cell leukemia
  • hepatitis E noro (infectious gastroenteritis)
  • polio acute leukomyelitis
  • hepatitis A coxsackie (hand-foot-and-mouth disease, herpangina), rhino (cold), etc. It is done.
  • reoviridae exists as a double-stranded RNA virus (without an envelope).
  • rotavirus belongs to the family Reoviridae. Examples of viral diseases caused by double-stranded RNA viruses include rota (sensitive gastroenteritis).
  • Rotavirus is an RNA virus belonging to the genus Rotavirus of the Reoviridae family.
  • Rotavirus particles consist of double-shell particles composed of three layers: core, inner shell and outer shell, and have RNA polymerase and cap synthesis-related enzymes in the virus particles.
  • the core consists of proteins VP1, VP2, and VP3 and is covered by inner shell protein VP6 to form a single shell particle, and further covered by outer shell proteins VP4 and VP7 to form a double shell particle, that is, an infectious virus particle.
  • Rotaviruses are classified into 8 types of A to H groups according to the antigenicity of the inner shell protein VP6. Rotaviruses that have been reported to infect humans are mainly Group A to Group C.
  • Rotavirus infects intestinal epithelial cells of the human small intestine and causes changes in tissue lesions such as disruption and loss of microvilli. This inhibits water absorption from the intestines and causes diarrhea. It usually develops after an incubation period of about 48 hours and causes acute gastroenteritis mainly in infants. The main symptoms are diarrhea (no bloody or mucous stool), nausea, vomiting, fever, abdominal pain, usually healed naturally in about 1 to 2 weeks, but severe dehydration can lead to shock, electrolyte abnormalities, and sometimes death There is also.
  • RNA viruses including rotaviruses
  • Adsorption time when the virus adsorbs to the host cell
  • Invasion time when the adsorbed virus enters the cell
  • a “replication time” in which a new virus is replicated from the unshelled RNA
  • a “release time” in which the replicated virus is released from the cell.
  • Viruses do not have the materials necessary for the synthesis of nucleic acids and proteins, and always require living cells.
  • bacteria basically grow by two divisions, whereas viruses increase in number in a host cell infected with one particle.
  • a binding protein (ligand) on the surface of the virus binds to a receptor on the surface of the host cell. Infectivity to a virus depends on whether the host cell has a receptor for the virus. In the case of rotavirus, binding proteins (outer shell proteins VP4 and VP7) on the virus surface bind to receptors on the cell side.
  • binding proteins outer shell proteins VP4 and VP7
  • the virus In the “invasion period”, the virus is generally taken up into endosomes in the cell by the eating and drinking action (endocytosis) of the cell. Then, by acidification within the endosome, the binding protein (ligand) on the virus surface and the cell membrane of the host cell fuse.
  • the outer shell protein VP4 needs to be cleaved into protein VP5 and protein VP8 by a host cell-derived protease (trypsin). After this cleavage, protein VP8 first comes into contact with a molecule containing sialic acid (first receptor), and then protein VP5 and outer shell protein VP7 bind to integrin (second receptor), thereby allowing direct entry or endocytosis. It is thought to enter the cell by tosis.
  • first receptor a host cell-derived protease
  • the binding protein (capsid) of the virus that has entered the cell is degraded, and RNA is released in the host cell (shelling).
  • the virus particles apparently disappear, and this period is also called the dark period.
  • the outer shell proteins VP4 and VP7 are removed during cell entry.
  • the outer shell proteins VP4 and VP7 are detached, rearrangement of the inner shell protein VP6 released into the cell occurs, and RNA transcription is started.
  • RNA replication period unshelled RNA is taken into the nucleus of the host cell, and a large amount of new RNA is replicated. At the same time, a large amount of virus-specific protein is synthesized through RNA transcription (synthesis of mRNA).
  • an RNA-dependent RNA polymerase that functions as an RNA replication enzyme functions.
  • a protein synthesis system such as ribosome possessed by the host cell functions.
  • the replicated RNA and the synthesized protein are assembled in the cell, and a new virus is assembled (replicated).
  • release time the virus is released outside the host cell by budding by covering the cell membrane or nuclear membrane of the host cell or by dying the host cell (refer to Non-Patent Document 1 for details).
  • Norovirus is an RNA virus belonging to the family Caliciviridae, and has not been successfully infected with cultured cells or experimental animals, and humans are said to be the only susceptible animals.
  • Norovirus causes symptoms of acute gastrointestinal inflammation such as vomiting and diarrhea in humans, and it is excreted in the stool of patients for about 3-7 days after symptoms disappear. .
  • Norovirus is thought to infect human jejunal epithelial cells, causing ciliary atrophy and flattening, as well as detachment and shedding, resulting in diarrhea.
  • the incubation period is considered to be about 24 to 48 hours, and nausea, vomiting, and diarrhea are the main symptoms, but may also be accompanied by abdominal pain, headache, fever, chills, myalgia, sore throat, malaise, and the like. It relieves without the need for special treatment, but it is necessary to be careful about vomiting, dehydration and suffocation due to diarrhea in infants and the elderly, and others with weak physical strength.
  • norovirus there are no common antiviral drugs effective against norovirus, usually symptomatic treatment is performed, and hydration to prevent dehydration and nutrition to prevent physical exhaustion Is the center of treatment. In addition, it is difficult to identify norovirus infection from clinical symptoms alone.
  • the “euglena-derived substance” as an active ingredient of the antiviral agent of the present invention includes Euglena or a dried product of Euglena and a hot water extract, paramylon extracted from Euglena cells, paramylon powder, processed products of paramylon, etc. Is included.
  • Euglena cells it is desirable to use Euglena gracilis, particularly E. gracilis Z strain.
  • species such as Euglena gracilis krebs and Euglena gracilis barbatillas, mutant strain SM-ZK strain (chloroplast-deficient strain) of Euglena gracilis Z strain and var.
  • Bacillaris of these variants It may be ⁇ -1,3-glucanase, Euglena intermedia, Euglena piride, and other Euglenas such as Astaia longa derived from genetic mutants such as chloroplast mutants of seeds.
  • Euglena is widely distributed in fresh water such as ponds and swamps, and may be used separately from these, or any Euglena already isolated may be used.
  • Euglena according to the present invention includes all mutants thereof. These mutant strains include those obtained by genetic methods such as recombination, transduction, transformation and the like.
  • a culture solution for example, a culture solution to which nutrient salts such as a nitrogen source, a phosphorus source, and a mineral are added, for example, a modified Cramer-Myers medium ((NH4) 2HPO4 1.0 g / L, KH2PO4 1 0.0g / L, MgSO4 ⁇ 7H2O 0.2g / L, CaCl2 ⁇ 2H2O 0.02g / L, Fe2 (SO2) 3 ⁇ 7H2O 3mg / L, MnCl2 ⁇ 4H2O 1.8mg / L, CoSO4 ⁇ 7H2O 1.5mg / L L, ZnSO4 ⁇ 7H2O 0.4 mg / L, Na2MoO4 ⁇ 2H2O 0.2 mg / L, CuSO4 ⁇ 5H2O 0.02 g / L, thiamine hydrochloride (vitamin B1) 0.1 mg / L, thiamine hydrochloride (vitamin B1)
  • (NH4) 2HPO4 can be converted to (NH4) 2SO4 or NH3aq.
  • a known Hutner medium or Koren-Hutner medium prepared based on the description of Euglena Physiology and Biochemistry (Edited by Shozaburo Kitaoka, Society of Sciences Publishing Center) may be used.
  • the pH of the culture solution is preferably 2 or more, and the upper limit thereof is preferably 6 or less, more preferably 4.5 or less.
  • the photosynthetic microorganisms can grow more dominantly than other microorganisms, so that contamination can be suppressed.
  • Euglena cells may be cultured by an open pond method using sunlight directly, a light collecting method in which sunlight condensed by a light concentrator is sent through an optical fiber, etc., and irradiated in a culture tank and used for photosynthesis.
  • Euglena cells can be cultured using, for example, a fed-batch method, but flask culture, fermentation using a fermentor, batch culture, semi-batch culture (fed-batch culture), continuous culture (perfusion) Any liquid culture method such as a culture method may be used. Euglena cells are separated by, for example, centrifugation of the culture medium or simple sedimentation.
  • Polyethylene is a high molecular weight polymer ( ⁇ -1,3-glucan) in which about 700 glucose is polymerized by ⁇ -1,3-linkage, and is a storage polysaccharide contained in the genus Euglena. It is. Paramylon particles are flat spheroid particles, and ⁇ -1,3-glucan chains are entangled in a spiral shape.
  • Paramylon exists as granules in Euglena cells of all species and varieties, and the number, shape, and uniformity of the particles are characterized by species.
  • Paramylon consists only of glucose, and the average degree of polymerization of paramylon obtained from a wild strain of E. gracilis Z and a chloroplast-deficient strain SM-ZK is about 700 in glucose units.
  • Paramylon is insoluble in water and hot water, but is soluble in dilute alkali, concentrated acid, dimethyl sulfoxide, formaldehyde, and formic acid.
  • the average density of paramylon is 1.53 for E. gracilis Z and 1.63 for E. gracilis var. Bacillaris SM-L1.
  • the particle size distribution of Paramylon (manufactured by Euglena Co., Ltd.) has a median diameter of 1.5 to 2.5 ⁇ m when measured with a laser diffraction / scattering particle size distribution analyzer.
  • Paramylon particles are isolated from the cultured Euglena cells by any appropriate method and purified into fine particles, and are usually provided as powders.
  • paramylon particles can be (1) cultured Euglena cells in any suitable medium; (2) separation of Euglena cells from the medium; (3) isolation of paramylon from isolated Euglena cells; 4) Purification of isolated paramylon; and (5) if necessary, can be obtained by cooling and subsequent lyophilization.
  • Paramylon isolation is performed, for example, using non-ionic or anionic surfactants of the type that are largely biodegradable.
  • the purification of paramylon is performed substantially simultaneously with the isolation.
  • Examples of the “processed product of paramylon” include amorphous paramylon and emulsion paramylon.
  • “Amorphous paramylon” is a substance obtained by amorphizing crystalline paramylon derived from Euglena. Amorphous paramylon has a relative crystallinity of 1 to 20% with respect to crystalline paramylon produced by a method known from Euglena. However, this relative crystallinity was determined by the method described in Japanese Patent No. 5612875.
  • Amorphous paramylon is an alkali-treated product prepared by subjecting crystalline paramylon powder to an alkali treatment, neutralization with an acid, followed by washing, moisture removal, and drying in accordance with the method described in Japanese Patent No. 5612875. It is.
  • Emulsion paramylon is a substance called emulsion paramylon because its processing method and physical properties are similar to those of emulsions, and the fluid obtained by adding water to paramylon is ejected from the pore nozzle at ultra high pressure. It is a processed paramylon that is obtained by performing a collision process to collide with an object to be collided and swelled by being combined with water four times or more.
  • Emulsion paramylon is a known physical property reforming apparatus (for example, Japanese Patent Application Laid-Open No. 2011-88108) in which a slurry obtained by adding a water-soluble solvent to a solid such as powder is ejected from a pore nozzle at an ultrahigh pressure to collide with a collision target.
  • Emulsion paramylon has a median diameter of at least 5 times that of paramylon when measured with a laser diffraction / scattering particle size distribution analyzer, and is at least 7 ⁇ m. It is observed that it adheres, and swells by combining with water four times or more than paramylon. Slurry mixed with raw material paramylon and water is a free-flowing fluid, but emulsion paramylon is dispersed in water molecules, the viscosity increases and becomes viscous, and when touched, it adheres to the hand.
  • the obtained processed paramylon is referred to as emulsion paramylon in this specification, but it is unclear whether it is emulsified, and the state where paramylon is combined with water and swells. It is.
  • paramylon Other processed products of paramylon include water-soluble paramylon obtained by chemically or physically treating paramylon by various known methods, sulfated paramylon, and paramylon derivatives.
  • the antiviral agent exerts an antiviral action through an inhibitory action on the virus growth of the Euglena-derived substance, particularly an inhibitory action on the RNA virus growth.
  • the specific mechanism of action is as follows. (1) The Euglena-derived substance is produced when the binding protein (ligand) on the surface of the virus binds to a receptor (receptor) on the surface of the host cell during the “adsorption period” of the RNA virus growth process. It acts to inhibit adsorption to host cells. Specifically, when the RNA virus is a rotavirus, the Euglena-derived substance functions to inhibit the activity of binding proteins (outer shell proteins VP4, VP7) and specific enzymes involved in the adsorption time of the virus.
  • binding proteins outer shell proteins VP4, VP7
  • the Euglena-derived substance is a host of the virus when the RNA replicated in the “replication period” of the RNA virus growth process and the synthesized protein are assembled and a new virus is assembled. It acts to inhibit replication in the cell. Specifically, when the RNA virus is a rotavirus, the Euglena-derived substance functions to inhibit the activity of binding proteins and specific enzymes involved in the replication period of the virus.
  • Euglena-derived substances which are the main active ingredients of antiviral agents, inhibit the virus growth at least at the “adsorption time” and “replication time” of the virus growth process as an action that conventional antiviral agents do not have. Acts. Therefore, compared with conventional antiviral agents that exhibit antiviral activity only during a specific period of the virus growth process, this antiviral agent can be used at the first half of the virus growth process. Moreover, even if it is the second half replication period, it becomes possible to exhibit antiviral activity.
  • the antiviral agent of the present embodiment can be used as a therapeutic agent for a viral infection or a therapeutic agent for a viral disease by being administered to a viral infection patient or a non-human animal suffering from a viral infection. it can. Further, it can also be used as a prophylactic agent for viral infections and as a prophylactic agent for viral diseases in humans before suffering from viral infections, humans of the virus infection reserve army, animals other than these humans. Moreover, the antiviral agent of this embodiment can also be used as a prophylactic or therapeutic agent for infectious gastroenteritis that uses a virus as a pathogen.
  • the antiviral agent of this embodiment is desirably administered to patients infected with rotavirus and norovirus, among viruses.
  • rotavirus it is preferably administered to a patient infected with a group A rotavirus, and the virus is preferably a group A rotavirus Wa strain (G1P [8]).
  • the antiviral agent of this embodiment can be used as a composition such as a pharmaceutical composition or a food composition containing an antiviral agent that exerts the above-described effects on rotavirus and norovirus, among viruses. it can.
  • a composition such as a pharmaceutical composition or a food composition containing an antiviral agent that exerts the above-described effects on rotavirus and norovirus, among viruses. it can.
  • (Pharmaceutical composition) In the field of medicine, pharmacologically, together with an amount of Euglena-derived substance capable of effectively exerting an action of inhibiting virus growth, that is, an action of inhibiting the adsorption of viruses to host cells or an action of inhibiting the release of viruses from host cells.
  • action is provided by mix
  • the pharmaceutical composition may be a pharmaceutical or a quasi drug.
  • the pharmaceutical composition may be applied internally or externally.
  • the pharmaceutical composition is used in a pharmaceutical form such as an internal preparation, intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection and / or intraperitoneal injection, transmucosal application agent, transdermal application agent, and the like.
  • a pharmaceutical form such as an internal preparation, intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection and / or intraperitoneal injection, transmucosal application agent, transdermal application agent, and the like.
  • the dosage form of the pharmaceutical composition can be appropriately set depending on the form of application, for example, solid preparations such as tablets, granules, capsules, powders, powders, liquid preparations such as liquids and suspensions, Semi-solid preparations such as ointments or gels are mentioned.
  • an effective amount of Euglena-derived substance capable of exhibiting the action of inhibiting virus growth in vivo can be provided as a food material to provide a food composition having the action.
  • the present invention can provide a food composition labeled as virus growth inhibitory or the like in the field of food.
  • the food composition include foods for specified health use, functional nutritional foods, functional labeling foods, hospital patient foods, and supplements in addition to general foods. It can also be used as a food additive.
  • Examples of the food composition include seasonings, processed meat products, processed agricultural products, beverages (soft drinks, alcoholic beverages, carbonated beverages, milk beverages, fruit juice beverages, tea, coffee, nutritional drinks, etc.), powdered beverages (powder) Juice, powdered soup, etc.), concentrated beverages, confectionery (candy (throat cake), cookies, biscuits, gum, gummi, chocolate, etc.), bread, cereal and the like.
  • nutritional functional food, functional indication food, etc. it may be in the form of capsule, troche, syrup, granule, powder or the like.
  • food for specified health use is a food containing health functional ingredients that affect physiological functions, etc., and can be used to indicate that it is suitable for specific health use with the permission of the Commissioner of the Consumer Affairs Agency. is there.
  • it is a food that is sold as a specific health use, indicating the prevention and treatment of viral infections, inhibition of virus growth, prevention and treatment of infectious gastroenteritis, and the like.
  • the nutritional functional food is a food used for supplementing nutritional components (vitamins and minerals) and displays the function of the nutritional components. In order to sell as a functional nutritional food, the amount of nutrients contained in the daily intake standard amount must be within the specified upper and lower limits. You also need to.
  • the functional labeling food is a food that displays the functionality based on the scientific basis at the responsibility of the operator. Information on safety and functionality grounds was reported to the Commissioner of the Consumer Affairs Agency before sales.
  • the present invention includes a Euglena-derived substance as an active ingredient, a virus-infected patient, a food for specified health use for an antiviral agent intended for a non-human animal suffering from a viral infection, or an antiviral nutritional food It can be used as an antiviral functional food.
  • the present invention also includes a specific health for an antiviral agent containing a Euglena-derived substance as an active ingredient and intended for a living body, for example, a human before suffering from a viral infection, a human in a virus infection reserve army, or an animal other than these humans. It can be used as a food for food, a nutritional functional food for antiviral agents, and a functional labeling food for antiviral agents.
  • the antiviral agent of the present embodiment for example, in the case of rotavirus or norovirus, prescription is made so that the antiviral agent dissolves in the intestine (so as not to dissolve in the stomach) because it is easily infected in the human intestine. Good. For example, it may be administered orally by capsules, tablets, granules or syrups.
  • Euglena gracilis powder (manufactured by Euglena Co., Ltd.) was used as the Euglena-derived substance.
  • a Euglena solution (100 mg / ml) was prepared by dissolving 100 mg of the Euglena gracilis powder in 1 ml of ethanol and filtering with a 0.45 ⁇ M sterilizing filter. The solution was used as an antiviral agent.
  • Example 2 A hot water extract of Euglena as a Euglena-derived substance was prepared by the following procedure. Euglena gracilis powder (manufactured by Euglena Co., Ltd.) was extracted with hot water under normal pressure and then filtered under reduced pressure to separate the residue to obtain a hot water extract. The prepared hot water extract was filtered through a 0.45 ⁇ M sterilizing filter to obtain a Euglena hot water extract (stock solution). The extract was used as an antiviral agent.
  • Euglena gracilis powder manufactured by Euglena Co., Ltd.
  • the prepared hot water extract was filtered through a 0.45 ⁇ M sterilizing filter to obtain a Euglena hot water extract (stock solution).
  • the extract was used as an antiviral agent.
  • Example 3 Paramylon as a Euglena-derived substance was prepared by the following procedure. Euglena gracilis powder (manufactured by Euglena) was placed in distilled water and stirred at room temperature for 2 days. This was sonicated to break the cell membrane, and crude paramylon particles were recovered by centrifugation. The collected paramylon particles are dispersed in a 1% sodium dodecyl sulfate aqueous solution and treated at 95 ° C. for 2 hours. The paramylon particles collected by centrifugation again are dispersed in a 0.1% sodium dodecyl sodium sulfate aqueous solution and treated at 50 ° C. for 30 minutes. did.
  • lipids and proteins were removed by this operation, then washed with acetone and ether, and then dried at 50 ° C. to obtain purified paramylon particles.
  • 100 mg of the prepared paramylon powder was dissolved in 1 ml of dimethyl sulfoxide (DMSO) and filtered through a 0.45 ⁇ M sterilizing filter to obtain a paramylon solution (100 mg / ml). The solution was used as an antiviral agent.
  • DMSO dimethyl sulfoxide
  • Amorphous paramylon (a substance treated with alkali of paramylon) as a Euglena-derived material was prepared by the following procedure.
  • the paramylon powder prepared in Example 2 was dissolved by adding 5% (w / v) to 1N aqueous sodium hydroxide solution, stirred with a stirrer for 1 to 2 hours, and alkali-treated. Thereafter, 1N hydrochloric acid was added dropwise to a 1N sodium hydroxide aqueous solution in which paramylon powder was dissolved to neutralize it. After centrifugation, the supernatant was discarded, and the step of washing the precipitate with distilled water was repeated.
  • the precipitated gel was collected, frozen, and lyophilized with a freeze dryer to obtain amorphous paramylon.
  • 10 mg of the prepared amorphous paramylon powder was dissolved in 1 ml of dimethyl sulfoxide (DMSO) and filtered through a 0.45 ⁇ M sterilizing filter to obtain an amorphous paramylon solution (10 mg / ml).
  • DMSO dimethyl sulfoxide
  • the solution was used as an antiviral agent.
  • Example 1 Infection inhibition test during rotavirus growth process> Using the antiviral agents of Examples 1 to 4, a test was conducted to confirm the action of inhibiting rotavirus growth.
  • MA-104 cells rhesus monkey kidney cells
  • rotavirus Wa strain G1P [8]
  • DMEM Dulbecco containing 10% FBS (Fetal Bovine Serum) is used as the liquid medium.
  • 's Modified Eagle Medium was used.
  • MA-104 cells were respectively seeded on a 24-well plate so as to be 1.0 ⁇ 10 4 cells / well, and were subjected to monolayer culture at 37 ° C. and 5% CO 2 for 24 hours.
  • the cultured MA-104 cells were infected with rotavirus at 0.1 moi (multiplicity of infection) and left at room temperature for 1 hour (adsorbed). Thereafter, the Euglena solution of Example 1 was added to the liquid medium so as to contain a predetermined concentration, and cultured in a CO 2 incubator for 48 hours.
  • the virus growth inhibition rate (%) was calculated.
  • the concentration (IC50) of an antiviral agent that inhibits viral infection of cells by 50% was calculated.
  • (1) a culture obtained by adding the Euglena hot water extract of Example 2 and (2) a culture obtained by adding the paramylon solution of Example 3 (3) an amorphous paramylon solution of Example 4 The virus growth inhibition rate was calculated in the same manner for each of those cultured with the addition of.
  • FIG. 1 shows a graph comparing the virus growth inhibition rates of each concentration (0.1 mg / ml, 1.0 mg / ml, 2.0 mg / ml) by Euglena (Example 1) by analyzing the test results. .
  • the virus growth inhibition rate at each concentration was 40.4%, 96.8%, and 98.0% in this order, and the IC50 was 0.66 mg / ml.
  • the virus growth inhibition rate further increased with increasing Euglena concentration.
  • the “euglena concentration of 0.1 mg / ml” indicates a concentration containing 0.1 mg of euglena with respect to 1 ml of the liquid medium. In other words, the Euglena solution (100 mg / ml with respect to the liquid medium). ) Indicates a concentration of 0.1% by volume.
  • FIG. 2 the graph which compared the virus growth inhibition rate of each density
  • concentration 0.02 mg / ml, 0.04 mg / ml, 0.06 mg / ml
  • concentration 0.02 mg / ml, 0.04 mg / ml, 0.06 mg / ml
  • concentration 0.02 mg / ml, 0.04 mg / ml, 0.06 mg / ml
  • FIG. 3 shows a graph comparing the virus growth inhibition rates at various concentrations (0.1 mg / ml, 1.0 mg / ml, 2.0 mg / ml) with paramylon (Example 3).
  • the virus growth inhibition rate at each concentration was 0%, 17.8%, and 30.1% in order.
  • the virus growth inhibition rate further increased with increasing paramylon concentration.
  • FIG. 4 shows a graph comparing the virus growth inhibition rates at various concentrations (0.1 mg / ml, 1.0 mg / ml, 2.0 mg / ml) with amorphous paramylon (Example 4).
  • the virus growth inhibition rate at each concentration was 3.8%, 33.3%, and 53.4%, respectively, and the IC50 was 1.74 mg / ml.
  • the virus growth inhibition rate further increased as the concentration of amorphous paramylon increased.
  • amorphous paramylon (paramylon alkali-treated product) inhibited rotavirus growth at a lower concentration than paramylon. From this, it was found that many substances obtained by alkali treatment of paramylon have an action of inhibiting rotavirus growth.
  • the preferred concentration of Euglena in the action of inhibiting rotavirus growth is 0.1 mg / ml or more, and the more preferred concentration (IC50) is 0.66 mg / ml or more. It was. It was found that a suitable concentration (IC50) of Euglena hot water extract was 0.012 mg / ml or more.
  • the preferred concentration of paramylon was found to be 2.0 mg / ml or higher. It was found that the preferred concentration of amorphous paramylon was 1.0 mg / ml or more, and the more preferred concentration (IC50) was 1.74 mg / ml or more.
  • an antiviral agent containing Euglena as a Euglena-derived substance at a concentration of at least 0.66 mg / ml is dissolved in the intestine (so as not to dissolve in the stomach), a capsule, It has been found that it can be administered orally by tablets, granules or syrups.
  • the feline calicivirus is a virus that is widely used as an alternative virus for norovirus that cannot be cultured in cells.
  • CRFK cells Cells and media CRFK cells (Dainippon Pharmaceutical Co., Ltd.) were used as host cells, and feline calicivirus F-9 strain (Fine ATCC VR-782) was used as a virus.
  • FBS Fetrachloride
  • As the cell growth medium Eagle's MEM medium “Nissui” 1 (Nissui Pharmaceutical Co., Ltd.) added with 10% FBS was used.
  • As the cell maintenance medium Eagle's MEM medium “Nissui” 1 added with 2% FBS was used.
  • -Cell culture CRFK cells were cultured in a monolayer in a tissue culture flask using a cell growth medium. -Inoculation of virus After monolayer culture, the cell growth medium was removed from the flask and inoculated with feline calicivirus. Next, cell maintenance medium was added and cultured in a carbon dioxide incubator (CO 2 concentration: 5%) at 37 ° C. ⁇ 1 ° C. for 1 to 5 days. -Preparation of virus suspension After culturing, the morphology of cells was observed using an inverted phase contrast microscope, and it was confirmed that morphological changes (cytopathic effect) occurred in the cells. Next, the culture solution was centrifuged (3000 rpm / min, 10 minutes), and the resulting supernatant was used as a virus suspension.
  • Example 2 The specimen suspension of Euglena powder (prepared using 99.5% ethanol) of Example 1 was allowed to stand, and the supernatant obtained was diluted with a cell maintenance medium to obtain a specimen solution.
  • the virus solution was diluted 10-fold with the sample solution diluted with the cell maintenance medium, and the virus infectivity titer was measured. In addition, about the control, it tested similarly using a cell maintenance medium.
  • CRFK cells were monolayer-cultured in a tissue culture microplate (96 well) using a cell growth medium, and then 0.1 ml each of a sample solution or a cell maintenance medium was added except for the cell growth medium. Next, 0.1 ml of the working fluid dilution was inoculated into each 4 wells and cultured in a carbon dioxide incubator (CO 2 concentration: 5%) at 37 ° C. ⁇ 1 ° C. for 4-7 days.
  • CO 2 concentration CO 2 concentration: 5%
  • TCID50 tissue culture infectious dose
  • Test Example 2 The results of Test Example 2 are shown in Table 1. “TCID 50 ” in Table 1 means 50% tissue culture culture dose, and “log TCID 50 / ml” indicates the common logarithm of TCID 50 per mL of working solution. Note that no cytopathic effect was observed at a sample concentration of 0.5 mg / ml. The measurement was performed 3 times, and p ⁇ 0.05 by t-test.

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Abstract

La présente invention concerne un agent antiviral et un aliment antiviral en tant que nouveaux procédés d'utilisation d'une substance dérivée d'euglène. L'agent antiviral et l'aliment antiviral, comprenant tous deux une substance dérivée d'euglène en tant que substance active, sont destinés à être utilisés pour prévenir ou traiter une maladie infectieuse causée par un virus à ARN sans enveloppe. Des exemples du virus à ARN sans enveloppe comprennent des rotavirus appartenant aux Reoviridae. Des exemples de la substance dérivée d'euglène comprennent de l'euglène, un extrait d'eau chaude d'euglène, le paramylon et un paramylon traité par un alcali.
PCT/JP2016/084571 2016-03-04 2016-11-22 Agent antiviral et aliment antiviral WO2017149858A1 (fr)

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